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Peptidylarginine deiminase type 4 deficiency reduced arthritis severity in a glucose-6-phosphate isomerase-induced arthritis model.

Seri Y, Shoda H, Suzuki A, Matsumoto I, Sumida T, Fujio K, Yamamoto K - Sci Rep (2015)

Bottom Line: Peptidyl arginine deiminase 4 (PAD4) is an enzyme that is involved in protein citrullination, and is a target for anti-citrullinated peptide antibodies (ACPAs) in rheumatoid arthritis (RA).Genetic polymorphisms in the PADI4 gene encoding PAD4 are associated with RA susceptibility.Furthermore, the survival of Padi4-deficient neutrophils was impaired in vitro.

View Article: PubMed Central - PubMed

Affiliation: Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Bunkyo-ku, Tokyo, 113-8655, Japan.

ABSTRACT
Peptidyl arginine deiminase 4 (PAD4) is an enzyme that is involved in protein citrullination, and is a target for anti-citrullinated peptide antibodies (ACPAs) in rheumatoid arthritis (RA). Genetic polymorphisms in the PADI4 gene encoding PAD4 are associated with RA susceptibility. We herein analyzed the roles of PADI4 in inflammatory arthritis using a glucose-6-phosphate isomerase (GPI)-induced arthritis (GIA) model in Padi4 knockout (KO) mice. Arthritis severity, serum anti-GPI antibody titers, and IL-6 concentrations were significantly reduced in Padi4 KO mice. The frequency of Th17 cells was decreased in GPI-immunized Padi4 KO mice, whereas WT and Padi4-deficient naïve CD4(+) T cells displayed the same efficiencies for Th17 cell differentiation in vitro. In addition, the numbers of myeloid lineage cells were reduced with the increased expression of pro-apoptotic genes in GPI-immunized Padi4 KO mice. Furthermore, the survival of Padi4-deficient neutrophils was impaired in vitro. Our results suggest that PADI4 exacerbates arthritis with diverse immunological modifications.

No MeSH data available.


Related in: MedlinePlus

Neutrophil and monocyte numbers after the GPI immunization.(A) The expression of Padi4 in CD11+ Ly-6G+ neutrophils (Neus), CD11+ Ly-6C+ Ly-6G− monocytes (MCs), CD3+ T cells, and CD19+ B cells was measured by quantitative PCR 7 days after the immunization (WT = 3, Padi4 KO = 3). (B) The numbers of Neus and MCs in spleens were counted 7 days after the immunization (WT n = 9, Padi4 KO n = 9). (C–F) Pro-apoptotic gene expression in Neus, MCs, T cell, and B cells was measured by quantitative PCR 7 days after the immunization (WT n = 3, Padi4 KO n = 3). Gray bars; WT, open bars; Padi4 KO. *p < 0.05.
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f6: Neutrophil and monocyte numbers after the GPI immunization.(A) The expression of Padi4 in CD11+ Ly-6G+ neutrophils (Neus), CD11+ Ly-6C+ Ly-6G− monocytes (MCs), CD3+ T cells, and CD19+ B cells was measured by quantitative PCR 7 days after the immunization (WT = 3, Padi4 KO = 3). (B) The numbers of Neus and MCs in spleens were counted 7 days after the immunization (WT n = 9, Padi4 KO n = 9). (C–F) Pro-apoptotic gene expression in Neus, MCs, T cell, and B cells was measured by quantitative PCR 7 days after the immunization (WT n = 3, Padi4 KO n = 3). Gray bars; WT, open bars; Padi4 KO. *p < 0.05.

Mentions: Previous studies demonstrated that the Padi4 gene was mainly expressed in myeloid lineage cells6. In the case of the GIA model, Padi4 was dominantly expressed in CD11b+ Ly-6G+ neutrophils (Neus) and CD11b+ Ly-6C+ Ly-6G− monocytes (MCs), not T cells or B cells (Fig. 6A). As shown in Fig. 1D, although the total cell numbers of splenocytes and iLN cells were significantly decreased in Padi4 KO GIA mice, the number of B cells or T cells remained unchanged in Padi4 KO mice (Figs 2A and 3A). In contrast, the numbers of Neus and MCs were significantly decreased in the spleens of Padi4 KO mice 7 days after the rhGPI immunization (Fig. 6B). Furthermore, the expression of pro-apoptotic genes, such as Bid, Bad, and Bax, was increased in Padi4-deficient Neus and MCs from rhGPI-immunized mice (Fig. 6C,D). The expressions of these pro-apoptotic genes were not different in the lymphoid lineage cells (Fig. 6E,F). Moreover, the survival of PADI4-deficient Neus, not MCs, was impaired in the in vitro culture with or without the LPS stimulation (Fig. 7). These results suggested that PADI4 controls the survival of myeloid lineage cells.


Peptidylarginine deiminase type 4 deficiency reduced arthritis severity in a glucose-6-phosphate isomerase-induced arthritis model.

Seri Y, Shoda H, Suzuki A, Matsumoto I, Sumida T, Fujio K, Yamamoto K - Sci Rep (2015)

Neutrophil and monocyte numbers after the GPI immunization.(A) The expression of Padi4 in CD11+ Ly-6G+ neutrophils (Neus), CD11+ Ly-6C+ Ly-6G− monocytes (MCs), CD3+ T cells, and CD19+ B cells was measured by quantitative PCR 7 days after the immunization (WT = 3, Padi4 KO = 3). (B) The numbers of Neus and MCs in spleens were counted 7 days after the immunization (WT n = 9, Padi4 KO n = 9). (C–F) Pro-apoptotic gene expression in Neus, MCs, T cell, and B cells was measured by quantitative PCR 7 days after the immunization (WT n = 3, Padi4 KO n = 3). Gray bars; WT, open bars; Padi4 KO. *p < 0.05.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4544002&req=5

f6: Neutrophil and monocyte numbers after the GPI immunization.(A) The expression of Padi4 in CD11+ Ly-6G+ neutrophils (Neus), CD11+ Ly-6C+ Ly-6G− monocytes (MCs), CD3+ T cells, and CD19+ B cells was measured by quantitative PCR 7 days after the immunization (WT = 3, Padi4 KO = 3). (B) The numbers of Neus and MCs in spleens were counted 7 days after the immunization (WT n = 9, Padi4 KO n = 9). (C–F) Pro-apoptotic gene expression in Neus, MCs, T cell, and B cells was measured by quantitative PCR 7 days after the immunization (WT n = 3, Padi4 KO n = 3). Gray bars; WT, open bars; Padi4 KO. *p < 0.05.
Mentions: Previous studies demonstrated that the Padi4 gene was mainly expressed in myeloid lineage cells6. In the case of the GIA model, Padi4 was dominantly expressed in CD11b+ Ly-6G+ neutrophils (Neus) and CD11b+ Ly-6C+ Ly-6G− monocytes (MCs), not T cells or B cells (Fig. 6A). As shown in Fig. 1D, although the total cell numbers of splenocytes and iLN cells were significantly decreased in Padi4 KO GIA mice, the number of B cells or T cells remained unchanged in Padi4 KO mice (Figs 2A and 3A). In contrast, the numbers of Neus and MCs were significantly decreased in the spleens of Padi4 KO mice 7 days after the rhGPI immunization (Fig. 6B). Furthermore, the expression of pro-apoptotic genes, such as Bid, Bad, and Bax, was increased in Padi4-deficient Neus and MCs from rhGPI-immunized mice (Fig. 6C,D). The expressions of these pro-apoptotic genes were not different in the lymphoid lineage cells (Fig. 6E,F). Moreover, the survival of PADI4-deficient Neus, not MCs, was impaired in the in vitro culture with or without the LPS stimulation (Fig. 7). These results suggested that PADI4 controls the survival of myeloid lineage cells.

Bottom Line: Peptidyl arginine deiminase 4 (PAD4) is an enzyme that is involved in protein citrullination, and is a target for anti-citrullinated peptide antibodies (ACPAs) in rheumatoid arthritis (RA).Genetic polymorphisms in the PADI4 gene encoding PAD4 are associated with RA susceptibility.Furthermore, the survival of Padi4-deficient neutrophils was impaired in vitro.

View Article: PubMed Central - PubMed

Affiliation: Department of Allergy and Rheumatology, Graduate School of Medicine, the University of Tokyo, Bunkyo-ku, Tokyo, 113-8655, Japan.

ABSTRACT
Peptidyl arginine deiminase 4 (PAD4) is an enzyme that is involved in protein citrullination, and is a target for anti-citrullinated peptide antibodies (ACPAs) in rheumatoid arthritis (RA). Genetic polymorphisms in the PADI4 gene encoding PAD4 are associated with RA susceptibility. We herein analyzed the roles of PADI4 in inflammatory arthritis using a glucose-6-phosphate isomerase (GPI)-induced arthritis (GIA) model in Padi4 knockout (KO) mice. Arthritis severity, serum anti-GPI antibody titers, and IL-6 concentrations were significantly reduced in Padi4 KO mice. The frequency of Th17 cells was decreased in GPI-immunized Padi4 KO mice, whereas WT and Padi4-deficient naïve CD4(+) T cells displayed the same efficiencies for Th17 cell differentiation in vitro. In addition, the numbers of myeloid lineage cells were reduced with the increased expression of pro-apoptotic genes in GPI-immunized Padi4 KO mice. Furthermore, the survival of Padi4-deficient neutrophils was impaired in vitro. Our results suggest that PADI4 exacerbates arthritis with diverse immunological modifications.

No MeSH data available.


Related in: MedlinePlus